title: TNFα- and IL-17A-mediated S100A8 expression is regulated by p38 MAPK.
abstract: The antimicrobial peptide S100A8 is known to be upregulated in lesional psoriatic skin compared with non-lesional psoriatic skin and is believed to play a role in the pathogenesis of psoriasis. However, little is known about the signalling pathways involved in the regulation of S100A8 expression. Using quantitative real-time RT-PCR analysis, we demonstrated that stimulation with TNFα and IL-17A in combination resulted in a significant and synergistic induction of S100A8 mRNA in human keratinocytes. TNFα and IL-17A also induced the S100A8 promoter activity synergistically. This was demonstrated by a gene reporter assay in cells transfected with a luciferase plasmid construct, consisting of 3502 base pairs of the human S100A8 promoter. The TNFα- and IL-17A-mediated induction of S100A8 mRNA and protein was mediated by a p38 MAPK-dependent mechanism, as demonstrated by the use of a p38 MAPK inhibitor. Finally, adalimumab treatment for patients with psoriasis significantly decreased S100A8 mRNA at day fourteen after start of treatment, but not at day four. Taken together, this study demonstrates that the p38 MAPK signalling pathway plays a key role in the TNFα- and IL-17A-induced expression of S100A8 in cultured human keratinocytes.
authors.affiliation: Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark.
authors.forename: Maike
authors.initials: M
authors.lastname: Mose
authors.forename: Zhanyuan
authors.initials: Z
authors.lastname: Kang
authors.forename: Line
authors.initials: L
authors.lastname: Raaby
authors.forename: Lars
authors.initials: L
authors.lastname: Iversen
authors.forename: Claus
authors.initials: C
authors.lastname: Johansen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000068879:Adalimumab; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry; D001706:Biopsy; D040501:Calgranulin A / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology; D011401:Promoter Regions, Genetic; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D061067:Antibodies, Monoclonal, Humanized; D023181:Antimicrobial Cationic Peptides; D040501:Calgranulin A; C508717:IL17A protein, human; D020381:Interleukin-17; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000068879:Adalimumab